In 1984, when our daughter was born, she was diagnosed with congenital defects that included an abnormal heart. The heart condition is called Tetralogy of Fallot with Absent Pulmonary Valve. It is characterized by four heart anomalies and the missing valve that regulates blood coming from the heart and going into the lungs.
Fortunately, she survived the trauma of numerous hospitalizations, two open-heart operations, a valve implant done experimentally through a catheter, and a pregnancy; she is doing well physically and has a five-year-old, our granddaughter. The last experimental procedure was a stopgap supposed to last five years. It has endured well over twenty years and appears to still be in good shape.
Her travails made me study the science behind heart birth defects, which affect 8 to 10 per 1,000 child births. That number accounts only for those children receiving a clinical diagnosis of a congenital heart disease or defect (CHD). It doesn’t include those never diagnosed. That’s why the World Health Organization (WHO), in a 2026 report, states that the occurrence of CHD is almost twice as high, affecting between 1.4 and 2.3% of all children born each year globally, or almost 1 for every 50 live births.
CHD Defined
CHDs are structural abnormalities that are diagnosed in utero or after birth. Unlike acquired heart disease, which adults get, CHDs are physical defects in the walls that separate the heart’s four chambers, obstructions that block the major arteries, arterial transpositions and fusions, damaged or missing valves, and other malformations. CHDs cause rhythm disturbances. They damage the lungs and other major organs.
Sometimes, CHDs remain undetected until adulthood, often discovered incidentally or because of a different medical condition. Many CHDs, however, require early intervention, often within a week to a month after birth to ensure a child’s survival. Between 1990 and 2023, according to the WHO, CHD was a leading cause of infant mortality within the first 28 days after birth.
CHD Types
VSD
The most common CHD, representing up to 40% of all cases, is a hole in the wall that separates the two lower heart chambers called ventricles. This is a ventricular septal defect or VSD. The ventricles are the principal pumping chambers that push blood throughout the body.
ASD
The second most common CHD, up to 10%, involves holes in the wall separating the two upper chambers, the atria. This is an atrial septal defect or ASD. It often is missed as a diagnosis until adulthood.
PDA
A third CHD is Patent Ductus Arteriosus (PDA). Before birth, the PDA is a blood vessel that connects the placenta to the child’s circulatory system. With the first breaths causing the lungs to inflate, the natural pressure from this anatomical change forces the PDA to close, usually within hours, if not a few days. If the PDA doesn’t close, it compromises the lungs and reduces the amount of oxygen circulating through the body.
Children with a PDA at birth who live in high altitudes can be undiagnosed for years. Only when they descend to lower elevations do they become symptomatic as ambient air pressure rises, compromising the lungs.
Genetic and Developmental Triggers for CHD
When our daughter was diagnosed, the cardiologists at the time mentioned genetic mutations as one potential cause. Genetic causes of CHD mean changes occurring to DNA sequences. Some are called trisomies; others, microdeletions. These coding errors can be familial or result from viral pathogens disrupting normal cell functions.
Developmental triggers involve disruptions to the normal sequence of heart formation, occurring during the first 12 weeks of embryonic development. These are heritable modifications that influence gene activity and RNA function, leading to errors in timing and sequencing during the critical formation of the organ’s four chambers and attendant blood vessels.
Environmental Triggers for CHD
The most significant environmental factor affecting a developing fetus is a mother’s health prior to and during the next nine months. For example, maternal diabetes is a known trigger of CHD. Others include medications, nutritional deficiencies, illnesses, smoking, alcohol, and age.
Maternal exposure to environmental contaminants before and during pregnancy can trigger CHDs. These are not limited to exposure to high concentrations of airborne particulate matter, ground-level ozone, radon gas, solvents, herbicides, microplastics and other contaminants.
Cell Signalling, Mutated Proteins and CHD
What in our cells can trigger CHD? TAK1, TAB2 and PKA-Cα are proteins that impact signalling antennae which sit on the exterior of the cell wall.
Søren Tvorup Christensen is a Professor of Cell Biology at the Department of Biology, University of Copenhagen, where researchers have identified the above-mentioned three proteins and the signalling antennae that appear to be responsible for delivering molecular instructions to embryonic stem cells that develop into heart muscle cells.
An article in the journal PLOS Biology on August 4, 2026, describes the University’s research that uncovered the proteins and the signalling mechanism. Lars Allan Larsen, a professor in the University’s Department of Cellular and Molecular Medicine, in a presser, described what was found:
“We have discovered a new communication system on the exterior of the cell that is crucial for the proper formation of the heart during embryonic development. This finding changes our understanding of how congenital heart defects arise. You could say that we have identified an important cog in a highly complex machine.”
Working with zebrafish, mouse and human embryonic stem cells, as well as other lab-grown cell types, the research showed that the genes encoding TAK1 and, to a lesser extent, the other signalling proteins produced rare variants leading to multisystem disorders including heart development.
In zebrafish, the mutations of TAK1 and TAB2 caused cardiac and extracardiac developmental defects. In human patients with CHD, genetic analysis indicated similar mutational variants in TAK1 and TAB2 proteins. Abnormal skeletal and organ development appears to be a consequence of these protein mutations, which may explain our daughter’s additional birth defects along with the CHD.
Christensen’s summary comments attempt to sum up what their study discovered, stating:
“This may explain why some patients with congenital heart disease also have defects and related conditions affecting the brain, kidneys, and skeleton. The mechanism provides a unifying explanation for diseases that we have previously struggled to understand.”
